title: Effect of an asparagine-to-serine mutation at position 294 in neuraminidase on the pathogenicity of highly pathogenic H5N1 influenza A virus.
abstract: Like the histidine-to-tyrosine substitution at position 274 in neuraminidase (NA H274Y), an asparagine-to-serine mutation at position 294 in this protein (NA N294S) confers oseltamivir resistance to highly pathogenic H5N1 influenza A viruses. However, unlike viruses with the NA H274Y mutation, the properties of viruses possessing NA N294S are not well understood. Here, we assessed the effect of the NA N294S substitution on the replication and pathogenicity of human H5N1 viruses and on the efficacy of the NA inhibitors oseltamivir and zanamivir in mouse and ferret models. Although NA N294S-possessing H5N1 viruses were attenuated in mice and ferrets compared to their oseltamivir-sensitive counterparts, one of the infected ferrets died from systemic infection, demonstrating the potential lethality in ferrets of oseltamivir-resistant H5N1 viruses with the NA N294S substitution. The efficacy of oseltamivir, but not that of zanamivir, against an NA N294S-possessing virus was substantially impaired both in ferrets and in vitro. These results demonstrate the considerable pathogenicity of NA N294S substitution-possessing H5N1 viruses and underscore the importance of monitoring the emergence of the NA N294S mutation in circulating H5N1 viruses.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.forename: Makoto
authors.initials: M
authors.lastname: Ozawa
authors.forename: Mai Thi Quynh
authors.initials: MT
authors.lastname: Le
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imai
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kakugawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.forename: Taisuke
authors.initials: T
authors.lastname: Horimoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001216:Asparagine / Q000235:genetics; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D005260:Female; D005289:Ferrets; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009439:Neuraminidase / Q000235:genetics* / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology / Q000627:therapeutic use; D017354:Point Mutation; D012376:Rodent Diseases / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D012694:Serine / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication; D053243:Zanamivir / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D037521:Virulence Factors; D053139:Oseltamivir; D012694:Serine; D001216:Asparagine; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D053243:Zanamivir